Benzenesulfonamido-halo-pyrimidines: antibacterials



United States Patent l 3,048,519 BENZENESULFONAMIDO-HALO-PYRWINES:ANTEBACTERIALS James L. Fedrick, Pearl River, and Gunnar S. Rodin,

New City, N.Y., and Robert G. Shepherd, Ridgewood, N.J., assignors toAmerican Cyanamid Company, New York, N.Y., a corporation of Maine NoDrawing. Filed Feb. 20, 1961, Ser. No. 90,245 Claims. (Cl. 167-515) Thisinvention relates to new compositions of matter. More particularly, itrelates to therapeutic compositions of substitutedbenzenesulfonamido-iodopyrimidines and a carrier.

In the development of sulfa drugs, sulfapyridine and sulfathiazole werefound to be active but also somewhat toxic. Other sulfa drugs weredeveloped which were more active, such as sulfadiazine andsulfamethazine. To avoid the requirement of dosage every four hours dayand night, more slowly excreted sulfa drugs have been sought. Thedesirable feature of slow excretion of sulfa drugs is commonly calledpersistence of activity. The persistent or long-acting sulfa drugs mostcommonly used now are 3-sulfanilamido-6-methoxypyridazine and4-sulfanilnols, acetone, Water, etc. These compounds are ordinarilypurified by dissolving in aqueous alkali and neutralizing the resultingsolution with aqueous acid.

It is unexpected that 2-sulfanilamido-S-iodopyrimidine would have highactivity and persistence of said activity when closely related compoundssuch as, for example, 2- sulfanilamido-5-bromopyrimidine and2-sulfanilamido-5- chloropyrimidine do not possess these properties.Single oral dosage in mice shows that the latter drugs are toxic to theextent of being about sixty times more toxic than the iodo derivativeand, in addition, are less active and less persistent. The high activityof 2-(p-nitrobenzenesulfonainido)-5-iodopyrimidine and of2-(p-acetamidobenzenesulfonamido)-5 iodopyrimidine is unexpected sinceit is well known [H. J. White et al., J. Pharmacol. 72, 112-122 (1941)],that such compounds are generally inactive. amido-S-iodopyrimidine, areso slowly excreted that they can be effectively used for prophylacticaction using infrequent dosages such as one dose per week. The presentcompositions are unusual in also giving extremely good antibacterialactivity both orally and subcutaneously.

The amount of single doses or daily doses to be given v would vary withthe size of the man or animal to be treated but should be such as togive a proportionate dosage of '1 to 500 mg./kg. per body weight. Interms of total weight of drug, this is usually from about 0.01 g. to10.00 g. per dosage unit. In larger animals, obviously, larger dosageunits may be desirable.

Experiments carried out using a single oral dose of various sulfa drugs24 hours before infection with Staphylococcus aureus shows that2-sulfanilamido-5-iodopyrimidine and2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine are greatly superior tothe commonly used These substances, and in particular 2-sulfanil-3,048,519 Patented Aug. 7, 1962 sulfa drugs. suits obtained.

TABLE I The Efiect of Single Oral Doses Given 24 Hours Before InfectionWith Staphylococcus aureus, Strain Smith Median efiec- Sulfa drug tivedoses,

rug/kg.

Sulfadiazine l Inactive 3-su1fanilamido-G-methoxypyridazine 8804-suIianilan1id0-2,G-dimethoxypyrinn 1 Inactive2-sultanilamido-5-iodopyrimidine 320 2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine 290 1 Inactive at the highest dose (1,280mg./kg.)

The present compositions containing 2-sulfanilamido- 5-iodopyrimidine,2-(p-acetamidobenzenesulfonamido)-5- iodopyrimidine and2-(p-nitrobenzenesulfonamido)-5- iodopyrimidine are effectiveantibacterial agents against infection with Staphylococcus aureus, acommonly-used test organism and with many other organisms as shownhereinafter. The new compositions containing2-(pacetamidobenzenesulfonamido)-5-iodopyrimidine show the best activitywhen used in a prophylactic fashion, e.g. oral dosage six to twenty-fourhours before infection.

TABLE II Prophylactic Treatment of Staphylococcus aureus InfectionTreatment Rcgaive Drug Percent an renal Single survival oral dose on14th potency day 320 100 160 S0 75 40 20 D0 20 152-(pacetamidobenzenesultonamido)- fi-iodopyrimidine a. 320 D 50 8O 10 405 2O 0 1 Treatment with the single oral doses shown six hours beforeinfection of mice.

The compositions of the present invention containing2-sulfanilamido-S-iodopyrimidine or2-(p-nitrobenzenesulfonamido)-5-iodopyrirnidine when tested against anumber of infections where the standard infection is given to mice andthe infected mice are treated by drug diet for seven days followed by aholding period of seven days, the following Table HI illustrates theresults obtained with the present compositions against variousinfections when compared to sulfadiazine.

N o'rE. Rel ative activities based on median effective doses against thevarious infections shown above. The standard infection given at 0 day;drug diet from 1 to +6 days; holding period 14 days after infection.

The following Table I illustrates the re The unexpected high activity ofthe present compositions such as 2-sulfanilamido-5-iodopyrimidine whentested along with the commonly used sulfa drugs shows the greatsuperiority of the present compositions over known sulfa drugs. Thesetests were conducted in mice and the infection used was Streptococcuspyogenes and Staphylococcus aureus. A summary of these tests is shown inthe following Table IV.

TABLE IV Percentage Survival of Infected Mice Treated With Various SulfaDrugs Treated with- Hour of dosing 2-sulfa- 2-su1fa-3,4-dlmethyle-sulfanil- 2,6-dimethoxy 3-sulfanilrelative to ni1amido-5-nilamido fi-sulfanilarmdo-l-phenyl 4-sulfanilarnldoG-rnethoxy infectioniodopyrimidine, pyrimidine, amido pyrazole, amido pyridazine,

percent percent lsoxazole, percent pyrimidine, percent percent percentGroup L- O 100 93 0 40 100 55 Group I -24 100 37 0 30 0 Group III -48 907 0 0 0 0 Group IV 72 90 7 Group V -96 70 0 In the above experiment theinfection is Streptococcus pj/ogenes, beta hemolytic strain 0203; 0.5ml. of a 1:100,000 broth dilution of a 5 hour blood-broth culture wasgiven intraperitoneally. The treatment: single subcutaneous dose of 500mg./kg. contained in 0.5 ml. of 0.2% aqueous agar; at time of infection(0 hours) or before infection (e.g 48 hours signifies 48 hours beforeinfection). Controls: 120 of 120 untreated infected mice were deadwithin 2 days after infection.

Treated with Hour of dosing 2-sulfa- 2-sulfa- 3,4-d1rnethylfi-sulfanil-2,6-dlmethoxy 3-sulfanilrelative to nilamido-onilamidos-sulfanilamido-l-phenyl 4-sulfanilamido-e-methoxy infectioniodopyrimidme, pyrimidine, amide pyrazole, amide pyridazine,

percent percent isoxazole, percent pyrimidine, percent percent percentGroup I 0 100 100 90 95 100 95 Group II 24 100 100 0 30 85 20 Group III48 100 55 0 0 10 Group IV 72 100 0 0 0 0 Group V 96 95 10 0 0 0 0 In theabove experiment the infection is Staphylococcus aureus, strain Smith:0.5 m1. of a 1:100 broth dilution of a 5 hour blood-broth culture wasgiven intraperitoneally. Treatment was a single Subcutaneous dose of 500mg./kg. contained in 0.5 ml of 0.2% aqueous agar at time of infection (0hours) or before infection as lndicated 1n hours (eg. 24, etc).Controls: 137 of 140 untreated infected mice were dead within 2 daysafter infection.

The sulfa drugs 2-sulfanilamido-5-iodopyrimidine, 2-p-acetamidobenzenesulfonamido)-5-iodopyrimidine and2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine can be combined with acarrier and dispensed in any of the usual dosage unit forms ofpharmaceutical preparations; for example, tablets, capsules, pills,suspension, as a power or in any other desirable form in therapeuticquantities hereinbefore given. In the preparation of tablets, forexample, the therapeutic agents may be combined with binders such as gumt-ragacanth, acacia, corn starch, gelatin etc. It is also usuallydesirable to have present a disintegrating agent such as, for example,corn starch, potato starch, alginic acid or the like. Also desirableusually is a lubricant such as stearic acid, magnesium stearate or talcalong with sweetening agents such as saccharin. Flavoring agents mayalso be used such as peppermint, oil of Wintergreen or cherry flavor.Larger tablets usually referred to as oblets of from 1-10 g. can be usedin veterinary medicines. In the preparation of capsules, fillers such asenumerated above for tablets can also be used. The compositions whenused in the form of suspensions or solutions may be combined withaqueous sugar or sorbitol type vehicle including a viscosity controlagent such as Veegum (magnesium aluminum silicate), methocel orcarboxymethylcellulose and a suitable perservative such as sodiumbenzoate or parabens (methyl and propyl p-hydroxybenzoic acid salts). Inthese liquid preparations, colorings, fiavorings and buffers can also beincluded to produce a more pharmaceutically elegant preparation. It isalso well-known in pharmaceutical practice to use a propylene glycoltype larger quantities from which single doses are withdrawn at the timeof use.

For use in veterinary medicine, the new compositions may be combinedwith edible carriers such as feed stuffs and so forth.

We claim:

1. A method of maintaining persistence of activity useful in thetreatment of ani-tbacterial infections which comprises administering indosage unit form from 1 mg. to 500 mg./kg. of body weight of a sulfadrug selected from the group consisting of2-sulfanilarnido-5-iodopyrimidine,2-(p-acctamidobenzenesulfonamido)-5-iodopyrimidine and2-(p-nitrobenzenesulfonamido)-S-iodopyrimidine and an edible carrier.

2. A method of maintaining persistence of acitvity against bacterialinfections which comprises introducing into the alimentary tract ofanimals having a bacterial infection, a therapeutic compositioncomprising from 1 mg. to 500 rug/kg. of body weight of2-sulfanilamido-5- iodopyrimidine and an edible carrier.

3. A method of maintaining persistence of activity against bacterialinfections which comprises parenterally administering into animalshaving a bacterial infection, a therapeutic composition comprising from1 mg. to 500 mg./kg. of body weight of 2-sulfanilarnido-S-iodopyrimidineand a parenteral vehicle.

4. A method of maintaining persistence of activity against bacterialinfections which comprises parenterally administering into animalshaving a bacterial infection, a therapeutic composition comprising from1 mg. to 500 mg./kg. of body weight of2-(p-acetamidobenzenesulfonamido)-5-idodopyrimidine and a parenteralvehicle. 5. A method of maintaining persistence of activity againstbacterial infections which comprises parenterally administering intoanimals having a bacterial infection, a therapeutic compositioncomprising from 1 mg. to 500 mg./kg. of body weight of2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine and a parenteral vehicle.

References Cited in the file of this patent Shepherd: ChemicalAbstracts, vol. 42, page 3409b, 1948, abs. of JACS, v01. 70, pp.157-160, 1948.

English et al.: JACS, v01. 68, March 1946, page 5 453-458.

English et al.: JACS, vol. 68, June 1946, pages 1039-1049.

1. A METHOD OF MAINTAINIG PERSISTENCE OF ACTIVITY USEFUL IN THETREATMENT OF ANITBACTERIAL INFECTIONS WHICH COMPRISES ADMINISTERING INDOSAGE UNIT FORM FROM 1 MG. TO 500 MG/KG OF BODY WEIGHT OF A SULFA DRUGSELECTED FROM THE GROUP CONSISTING OF 2-SULFANILAMIDO-5-IODOPYRIMIDINE,2-(P-ACETAMIDOBENZENESULFONAMIDO)-5-IODOPYRIMIDINE AND2-(P-NITROBENZENESULFONAMIDO)-5-IODOPYRIMIDINE AND AN EDIBLE CARRIER.